The major goals of this proposal are to identify and define virus and host factors important to the pathogenesis of AIDS. Of particular emphasis in the next project period will be an elucidation of the interactions between human cytomegalovirus (CMV) and human immunodeficiency virus type I (HIV-1) in the natural history and AIDS development and progression. There is substantial evidence that the vast majority of patients with AIDS are infected with both viruses. Interactions may take several forms (a) additive or synergistic immunosuppression or cytopathology (b) activation of one virus by the other (c) alteration of cell surface receptors to one virus by infection with the other (d) phenotypic mixing (e) viral recombination. CMV-HIV-1 interactions in vitro and in vivo will be explored. Cells dually infected will be studied for progeny CMV/HIV pseudotypes or recombinants by a variety of techniques including cross-neutralization, immune electron microscopy, and altered tropism determinations. Attempts will be made to rescue an envelope-deficient HIV-1 molecular construct from cells carrying it by use of a CMV envelope. Rescue analysis will be assessed by use of selective markers (resistance to mycophenolic acid), polymerase chain reaction assays of secondarily infected fibroblasts, and detection of HIV-1 antigen expression. In addition, the mechanisms underlying CMV transactivation of HIV-1 expression will be evaluated. in vivo interactions between CMV and HIV-1 will also be explored. Dually infected patients will have specimens (blood, semen) examined for CMV/HIV pseudotypes or recombinants. Autopsy brain and retinal specimens will also be studied. The tropism of CMV/HIV pseudotypes or recombinants derived from these sources will be evaluated on endothelial cell targets, as will the expression of novel receptors on such cells.